title: Targeting cathepsin E in pancreatic cancer by a small molecule allows in vivo detection.
abstract: When resectable, invasive pancreatic ductal adenocarcinoma (PDAC) is most commonly treated with surgery and radiochemotherapy. Given the intricate local anatomy and locoregional mode of dissemination, achieving clean surgical margins can be a significant challenge. On the basis of observations that cathepsin E (CTSE) is overexpressed in PDAC and that an United States Food and Drug Administration (FDA)-approved protease inhibitor has high affinity for CTSE, we have developed a CTSE optical imaging agent [ritonavir tetramethyl-BODIPY (RIT-TMB)] for potential intraoperative use. We show nanomolar affinity [half maximal inhibitory concentration (IC50) of 39.9 ± 1.2 nM] against CTSE of the RIT-TMB in biochemical assays and intracellular accumulation and target-to-background ratios that allow specific delineation of individual cancer cells. This approach should be useful for more refined surgical staging, planning, and resection with curative intent.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Keliher
authors.forename: Thomas
authors.initials: T
authors.lastname: Reiner
authors.forename: Sarah
authors.initials: S
authors.lastname: Earley
authors.forename: Jenna
authors.initials: J
authors.lastname: Klubnick
authors.forename: Carlos
authors.initials: C
authors.lastname: Tassa
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lee
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanahan
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Depinho
authors.forename: Cesar M
authors.initials: CM
authors.lastname: Castro
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
mesh_terms: D000818:Animals; D001706:Biopsy; D001896:Boron Compounds; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D020059:Cathepsin E / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D019438:Ritonavir / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D001896:Boron Compounds; D005456:Fluorescent Dyes; D017320:HIV Protease Inhibitors; D020059:Cathepsin E; D019438:Ritonavir